Abstract
The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/β-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose-dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down-regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased β-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer.
Highlights
Breast cancer is a common malignancy and ranks as the fourth leading cause of cancer mortality in women worldwide, with approximately 1.7 million new cases diagnosed every year[1]
To assess the effects of BHX on breast cancer cells, first we examined the cytotoxicity of BHX in human breast epithelial cell line MCF-10A (Fig. 2a)
Using the scratch-wound assay, we found that treatment of MDA-MB-231 cells with BHX resulted in a significant reduction in cellular migration compared to the cells treated with vehicle only
Summary
Breast cancer is a common malignancy and ranks as the fourth leading cause of cancer mortality in women worldwide, with approximately 1.7 million new cases diagnosed every year[1]. Suppressing proliferation and inhibiting breast cancer cell migration is considered to be an effective therapeutic strategy. Preclinical studies have shown that Wnt10b-driven activation of β-catenin stimulates the proliferation of metastatic breast cancer cells[8]. Metastasis, considered the primary cause of mortality in most cancer patients, is a multi-step process that involves the detachment of tumour cells from primary sites, cell migration via systemic circulation, extravasation to secondary sites, and further proliferation the metastatic cells to form new tumours[9]. BHX inhibited tumour cell proliferation, induced cell cycle arrest and apoptosis, decreased β-catenin protein levels, and increased E-cadherin expression[15]. The effects of BHX on breast cancer cells, and the specific molecules targeted by BHX responsible for its anti-tumour activity, are unknown. We attempt to elucidate the molecular pathways modulated by BHX that are necessary for its anti-tumour activity
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